Plasma proteomic biological themes correlated with changes in CAZyme gene abundances after consumption of the fiber-snack prototypes. (A) Schematic illustrating the distribution of plasma protein projections along singular vector 1 (SV1) from a CC-SVD analysis of the abundance of CAZyme genes versus changes in levels of plasma proteins after fiber snack consumption. Proteins with SV1 projections along the tails (α = 0.1) of the distribution are highlighted (green and red); these proteins, belonging to the 10th and 90th percentile groups, were analyzed using CompBio to identify biological themes enriched in each of the two percentile groups for each treatment. (B) Diagram illustrating pathways in which microbiome CAZyme-correlated plasma proteins (boldfaced) are involved in three interrelated biological themes (TGF-β/BMP-mediated fibrosis, P38/MAPK-associated immune biomarkers, and VEGF-mediated angiogenesis). (C, D) Network of biological themes identified from the CC-SVD and CompBio analysis. Themes are depicted as spheres; the number in each sphere corresponds to the theme enriched after pea or orange fiber treatment that is listed in SI Appendix,Dataset S6D. The size of a sphere is proportional to the CompBio enrichment score of its theme. The thickness of the lines connecting themes is proportional to the number of proteins shared between them. Purple spheres represent themes related to TGF-β-BMP signaling (fibrosis), p38/MAPK immune biomarkers, and VEGF-mediated angiogenesis that were enriched in the plasma proteomes of pea and orange fiber study participants (see Table 1).

a Clustering of transcriptomic profiles by principal component analysis of the AF tissues. FFive WT mice (two male; three female) and five Mut mice (two male; three female). b Hierarchical clustering of significantly differentially expressed genes (DEGs) (p < 0.05, ≥1.75-fold change). c Log-log scatterplots of DEGs in the AF. d i Themes associated with upregulated and downregulated DEGs are highlighted. The size of a sphere is related to its enrichment score and the thickness of the lines connecting themes signifies the number of genes shared between them. e-h CompBio analysis of DEGs and concepts whose abundances were significantly higher in ank AF cells. j–m Compbio analysis of DEGs and concepts whose abundances were significantly lower in ank AF cells.

Compared to control participants (n = 6), significant enrichments of Mtb-induced immune response themes (red spheres) were observed in BAL cells from LTBI individuals (n = 10, a) as well as in recipients of ID (n = 8, b) and PO ± ID BCG (n = 8, c). As presented in the table included with 4d (upper right), the mean ΔΔ gene expression changes for immune response genes in BAL were substantially more robust for recipients of PO ± ID BCG than for the other study groups; recipients of ID BCG alone displayed the most limited enrichment for immune themes. For the theme of T-cell stimulation, significant enrichment was seen in both LTBI and PO ± ID BCG groups; however, because the specific genes that accounted for identification of this theme differed so greatly between the two groups, heatmaps display the top ten genes enriched in LTBI individuals (top half, upper left) followed by the top ten enriched in recipients of PO ± ID BCG (bottom half, upper left). Notably, IL2 upregulation is strongly observed in LTBI individuals but not in recipients of PO ± ID BCG. Instead, the PO ± ID participants display upregulation of IL15, a potential alternative inducer of T cell proliferation (pink arrows). The additional heat maps in Fig. 4d indicate expression patterns for the top ten genes of a theme uniquely enriched in recipients of ID BCG (germinal centers, lower left heatmaps), and another uniquely expressed in those who received PO ± ID vaccination (MMPs/ECM, lower right heatmaps).

Representative images from whole slide images from (A) BEECH (EED) cohort and (B) US controls (Ctl). Zoomed-in views of the crypt base are shown in (C) and (D), respectively, to highlight Paneth cells. (E) Villous height:crypt depth ratio, (F) Paneth cells per crypt, and (G) goblet cells/enterocyte/villus in the BEECH cohort compared with controls. Statistical analysis was performed by Mann-Whitney tests. ***P < 0.001 and ****P < 0.0001. (H) Key dysregulated transcriptomic themes (both positively and negatively correlated with LAZ) in duodenum in the BEECH cohort as analyzed by CompBio. (I) Map of overlapping dysregulated transcriptomic themes between the BEECH and SEEM EED cohorts, as analyzed by Assertion Engine. Scale bars, (A and B) 50 μm and (C and D) 10 μm.

Transcriptomic profiling of BNIP3-deficient NP cells shows commonality with transcriptomes of a subset of degenerative human discs. (A, B) ShBnip3upregulated and down regulated themes showing similarity with transcriptome-based clusters generated from GSE70362 deposited microarray data based on histological grades. A pseudo heatmap showing global similarity as well as theme level similarity between transcriptional profiles of ShBnip3model and human clusters (GSE70362). FDR ≤0.05% and 2-fold change transcripts were used for the comparison study. (A) Pseudo heat map for upregulated DEGs (B) pseudo heat map for downregulated DEGs.